In 48 BC, the Roman Republic was decaying rapidly. Caesar had crossed the Rubicon River in the year before, starting a civil war. Pompey, Cato the younger and the rest of the conservative faction of the senate had fled to Greece. Caesar was preparing to follow in pursuit and, among other preparations, levied Legio IV. The first battles of the legion were Dyrrhachium and Pharsalus, where Caesar defeated Pompey. After this, the legion was stationed in the province of Macedonia, attaining thus its cognomen.

Octavian, now Augustus, sent the legion to Hispania Tarraconensis in 30 BC, to take part in the Cantabrian Wars. In 25 BC, they served as the decisive force in the Battle of Vellica under the personal command of Augustus.[2] After Augustus' victory in 13 BC, the legion remained in the province, but its effectives were spread through the Iberian Peninsula.

During the Batavian rebellion (69/70), IV Macedonica secured Moguntiacum and fought under Potillius Cerealis against the rebels. Their actions deserved no reproach but Vespasian did not trust its men, probably due to their support for Vitellius. The legion was disbanded in 70, but reconstituted shortly afterwards under the name of Legio IV Flavia Felix.